Loss of motor function linked to neurochemical biomarker: Study

Lower NAA associated with breakdown between primary motor cortex, other brain regions

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by Steve Bryson, PhD |

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A technician preps a patient for a MRI scan.

MRI scans of the brains of people with amyotrophic lateral sclerosis (ALS) have identified a neurochemical called N-acetyl aspartate (NAA) whose levels correlate with the loss of motor function, a study reports.

A drop in NAA levels was associated with the breakdown in communication between the primary motor cortex — the part of the brain that controls the muscles — and other brain regions. These reductions appeared to occur before structural changes in patients’ brains.

The findings suggest clinical imaging to detect NAA changes may be an effective, more sensitive marker of functional changes in ALS and provide an earlier diagnosis, the researchers noted.

“At this point brain imaging is not used in that way. It remains very much a research tool,”Sanjay Kalra, MD, study lead author and a professor at the University of Alberta (UA), Canada, said in a university news release. “The earlier we can make the diagnosis, the sooner we can start therapies and start counseling, and the sooner we can provide opportunities for enrollment in clinical trials.”

The MRI study, “Motor cortex functional connectivity is associated with underlying neurochemistry in ALS,” was published in the Journal of Neurology, Neurosurgery and Psychiatry.

Motor neurons are nerve cells in the brain and spinal cord that facilitate voluntary movement, such as walking, speaking, breathing, and swallowing. Upper motor neurons in the brain send signals via the spinal cord to lower motor neurons, which extend to communicate with the muscles.

In ALS, motor neurons are lost, impairing the ability of the brain, namely a region called the primary motor cortex, to communicate with muscles. This leads to symptoms like muscle weakness and difficulty with swallowing, speaking, and breathing.

Brain imaging studies have detected impaired communication between the primary motor cortex and the rest of the brain. This communication is referred to as functional connectivity, the degree to which different brain regions work together during a specific task or at rest.

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Impaired communication, motor neuron impairment

Researchers at UA and other Canadian centers hypothesized that such impaired communication could likely be attributed to issues with the structure or neurochemical properties of the upper motor neurons in the primary motor cortex.

“These upper motor neurons are thought to be more likely to be affected by the neurodegenerative process,” said Avyarthana Dey, study lead author and a PhD student at UA. “Because of their big size, they’re more vulnerable.”

The researchers collected imaging data on 52 ALS patients and 52 unaffected people matched in age, sex, and education from five academic hospitals affiliated with universities across Canada. Clinical data featured a foot tapping task to examine upper motor neuron function in the participants.

“One of the things that impedes research in single-center studies is that we only have a very small sample,” Dey said. “Having five different centers can capture a wider population with a more varied disease pattern.”

We postulate that the abnormality in NAA occurs before the occurrence of any apparent structural changes.

Foot tapping frequency was significantly reduced in ALS patients compared with controls, clinical assessments found. Patients also had impaired cognition and behavior compared with those without ALS.

Regarding symptoms of upper motor neuron involvement, 48 patients had an overactive reflex response in their lower limbs, 21 had an abnormal increase in muscle tone or stiffness (spasticity), and 15 had a foot reflex wherein the big toe flexes up instead of down.

Imaging results showed the primary motor cortex in patients had reduced functional connectivity compared with controls. NAA was also significantly reduced in the patients’ primary motor cortex.

An MRI imaging technique called diffusion tensor imaging (DTI), which measures the diffusion of water molecules in the brain’s white matter to examine structural changes, showed all measures were increased in the ALS patients.

One of these measures, fractional anisotropy, can be used to measure brain connectivity. Lower foot tapping frequency significantly correlated with both lower fractional anisotropy and lower NAA levels in the primary motor cortex, the researchers found.

Reduced NAA levels precede brain changes

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The association between clinical impairment and fractional anisotropy values was stronger than that with NAA levels. Still, functional connectivity was only correlated with NAA levels, suggesting they drop before white matter degenerates.

“We postulate that the abnormality in NAA occurs before the occurrence of any apparent structural changes,” Dey said.

“Clinical investigations could include assessments of primary motor cortical neurochemistry as an effective surrogate imaging marker of functional alterations in ALS,” the researchers wrote. “This might help provide an earlier diagnosis of ALS.”

An earlier diagnosis “significantly reduces the anxiety, stress, and panic that patients and their caregivers face when something is happening so quickly to them, when they’re losing function, yet no one can come up with a diagnosis,” Kalra said.

Future research could explore changes in the primary motor cortex during riluzole therapy (sold as Rilutek among other formulations), the researchers said.

Riluzole-based oral treatments can slow the progression of ALS and extend survival, and have been shown to increase NAA levels. Whether clinical outcomes and NAA levels are linked remains to be understood, however.

The researchers asked whether higher NAA levels with riluzole correlate with improved survival. “And if it does, by how much? Because right now riluzole has been shown to increase survival of patients, but we don’t know exactly how it does that,” Dey said.

More studies are needed to understand the correlation between NAA levels and loss of function, and how it’s impacted by ALS treatments, the researchers said.

“We’d like to know in future studies if improving neurochemistry with medication will improve functional connectivity,” Kalra concluded.